There Is No Longer Doubt: Zika Causes Microencephaly

New findings published yesterday leave little doubt about whether infection with the Zika virus during pregnancy can actually cause a serious birth condition in which a newborn has an abnormally small head (microcephaly) and abnormally small brain (microencephaly). Though researchers have strongly suspected the link, most have been urging caution in confirming it.

But a case report in the New England Journal of Medicine and a four-case series in the CDC’s Morbidity and Mortality Weekly Report appear to offer that confirmation with the Zika virus found in the brains of five newborns or fetuses whose mothers had been infected during pregnancy. In addition to the previous evidence of Zika virus present in two cases of amniotic fluid and the virus found in the blood and tissue of a newborn with microcephaly who died almost immediately, these findings show that the virus is vertically transmitted --from the mother to the infant -- and that it migrates to the brain.

“I am personally convinced by this study that Zika is vertically transmitted and infects the brains of infants, who then are born with microencephaly,” said Saul Hymes, MD, an assistant professor of clinical pediatrics in the Division of Pediatric Infectious Disease at Stony Brook Children's Hospital in New York. “That seems like a solid link to me.”

In NEJM, researchers from the University of Ljubljana in Slovenia report on an autopsy of a fetus aborted at 32 weeks of pregnancy after multiple ultrasounds confirmed microcephaly and suggested a poor outcome for the fetus. The 25-year-old mother had been a volunteer in Natal, the capital of the Brazilian state of Rio Grande do Norte. During her 13th week of pregnancy, she became sick with a high fever, muscle pain, pain behind the eyes and a rash, but she was never tested for Zika. Although her 14-week and 20-week ultrasounds showed normal fetal growth, another ultrasound at 29 weeks showed growth abnormalities. Further tests confirmed slowed fetal growth, a fetal head size below the 2nd percentile for that gestational week and calcification (hardened tissue from calcium deposits) in the fetal brain and placenta.

Three days after the pregnancy was terminated, an autopsy revealed microencephaly (an abnormally small brain) with severe underdevelopment, fluid build-up in the brain tissue and calcification. The researchers isolated the entire Zika virus genome from the brain tissue, and it matched that of the virus strain in Brazil.

In this Jan. 30, 2016 photo, Jose Wesley, who suffers from microcephaly, sleeps on a large pillow on his mother's bed in Bonito, Pernambuco state, Brazil. (AP Photo/Felipe Dana)

Hymes pointed out that the researchers eliminated other viruses and congenital infections as possible causes of the microencephaly and saw dense collections of viral proteins (inclusion bodies) in the neurons that make sense for explaining the damage that could cause severely slowed growth.

“In a perfect world, one would want to have an animal model and show that experimentally induced Zika vertical transmission leads to microencephaly,” Hymes said. “Additionally, it would be great to have clear case-control study data between infected and uninfected mothers showing the difference in microencephaly rates, controlling for as many other factors as possible. But I think those are merely ‘nice-to-haves’ and not necessary.”

The news also further convinces Mike Osterholm, director of the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota in Minneapolis. CIDRAP has one of the most extensive compilations of Zika resources.

“There appears to be clear evidence that this virus is a neurotropic virus—a virus infecting the neural tissue—and these findings are just more evidence of the fact that the Zika virus is causing microcephaly,” Osterholm said. “For many of us, there hasn’t been a question for some time,” he added.

Meanwhile, the CDC examined brain tissue and other tissues from two newborns with microcephaly who died in their first day of life and tissue from two fetuses lost during first-trimester miscarriages. All four mothers had a fever, rash and other symptoms of Zika during their first trimester of pregnancy

The fetuses and newborns all tested positive for Zika virus and all tested negative for dengue fever, another virus carried by the same species of mosquito. In the newborns, only their the brain tissue showed evidence of infection. Their brains also contained damaged nerve cells, calcified tissue and dead tissue (necrosis) from before the newborns’ deaths.

“None of this surprising,” Osterholm said. “What has been unfortunate is this debate for the last month of whether the link is proven or unproven. We had clear evidence for public health officials to take action a month ago.”

As reported by Nature last week, a pair of researchers from the Argentina-based Latin American Collaborative Study of Congenital Malformations (ECLAMC) published a report at the end of last year that suggested high levels of microcephaly overdiagnosis in Brazil, driven partly by increased awareness from Zika coverage and overly broad diagnostic criteria. Despite the uncertainty over how big the surge in cases is, however, Osterholm said he has no doubt that a surge has occurred.

“No one is saying that all the microcephaly cases are due to Zika, but the same doctors who were diagnosing a few cases a year went to multiple cases per week,” Osterholm said. He said some of the analyses of cases have misrepresented the outbreak’s effects because they have extrapolated numbers from the two main regions where Zika is circulating to the whole country.

It’s unclear whether these findings would necessarily change much in terms of policy measures, especially since the link was already so strongly suspected. It also does not mean that every pregnant woman who becomes infected with Zika will definitely give birth to a baby with serious problems. In Slate, Melinda Wenner Moyer offers a reality check for those in freak-out mode: The actual threat of microcephaly from cases of Zika in pregnancy may not be high. We don’t have good data on the risk yet.

The women whose children are most likely at risk are those who experienced symptoms from the infection early in their pregnancy. A report published by the CDC last month found that three out of four women whose babies were born with microcephaly had experienced a rash during their first or second trimester. (And four times as many women had the rash in the first trimester compared to the second trimester.)

So, many questions remain.

“The epidemiological data about when in pregnancy the transmission takes place, whether it matters if the mother is symptomatic or not and other questions are all things that will need to be answered, but they do not for me cast doubt on the central causal question,” Hymes said. “This report seems to answer that.”

Note: This post has been updated with a link and interchanging some paragraphs for clarity.

I am a freelance science and multimedia journalist who specializes in reporting on vaccines, pediatric and maternal health, parenting, public health, mental health, medical research, and the social sciences. My work has appeared in The New York Times, NPR, Scientific Americ...